Our long term goal is to help understand how Herpes Simplex viruses-1 and -2 (HSV-1 and HSV-2) bind to human cells and gain entry into those cells by membrane fusion. These viruses cause health problems in humans, which they persistently infect for life; most commonly causing oral and occular lesions (HSV-1) and genital lesions (HSV-2). We propose experiments designed to determine the atomic structure of the gD glycoprotein from the surface of HSV-1 (highly homologous to that of HSV-2) alone and in complex with three human cellular receptors. We also propose biochemical and structural experiments aimed at understanding changes in the structure of gD resulting from receptor binding and how these structural changes might impact other glycoproteins (gH/gL and gB) involved in viral entry into human cells. We also propose to design and test inhibitors of the virus-to-cell binding and experiments to examine the neutralization mechanism of a therapeutic antibody with the goal of improving its effectiveness.